ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption
Copyright policy )ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption
Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.
- King Abdulaziz University Saudi Arabia
- Yale University United States
- University of Toronto Canada
- University College London United Kingdom
- Hôpital Femme-Mère-Enfant France
Exome/genetics, Biomedical and clinical sciences, Nephrotic Syndrome, Ubiquinone, DNA Mutational Analysis, Drug Resistance, Sequence Homology, Protein Kinases/physiology*, Ubiquinone/analogs & derivatives*, Protein Kinases/genetics, Ubiquinone/biosynthesis, Ubiquinone/antagonists & inhibitors, Medical and Health Sciences, Consanguinity, Adrenal Cortex Hormones, 2.1 Biological and endogenous factors, Drosophila Proteins, Exome, Adolescent; Adrenal Cortex Hormones; Amino Acid Sequence; Animals; Cells, Cultured; Child; Consanguinity; Conserved Sequence; DNA Mutational Analysis; Disease Models, Animal; Drosophila Proteins; Drug Resistance; Exome; Fibroblasts; Gene Knockdown Techniques; Humans; Mitochondria; Molecular Sequence Data; Mutation; Nephrotic Syndrome; Podocytes; Protein Kinases; Rats; Sequence Alignment; Sequence Homology, Amino Acid; Ubiquinone; Young Adult; Zebrafish; Zebrafish Proteins, Aetiology, Child, Zebrafish, Cells, Cultured, Conserved Sequence, Fibroblasts/metabolism, Cultured, Podocytes, Ubiquinone/therapeutic use, Biological Sciences, Nephrotic Syndrome/drug therapy, Mitochondria, Amino Acid, Biological sciences, Nephrotic Syndrome/pathology, Podocytes/ultrastructure, Gene Knockdown Techniques, Drosophila Proteins/genetics, Nephrotic Syndrome/genetics*, Podocytes/metabolism, Adolescent, Cells, Immunology, Molecular Sequence Data, Renal and urogenital, 610, Adrenal Cortex Hormones/therapeutic use, Zebrafish Proteins/antagonists & inhibitors, Zebrafish/genetics, Drosophila Proteins/antagonists & inhibitors, Young Adult, Clinical Research, Zebrafish Proteins/genetics, Complementary and Integrative Health, Genetics, Mitochondria/physiology, Animals, Humans, Amino Acid Sequence, Biomedical and Clinical Sciences, Animal, Ubiquinone/metabolism, Health sciences, Adrenal Cortex Hormones/pharmacology, Zebrafish Proteins, Fibroblasts, Rats, Protein Kinases/deficiency, Disease Models, Animal, Nephrotic Syndrome/metabolism, Disease Models, Mutation, Zebrafish/embryology, Protein Kinases, Sequence Alignment
Exome/genetics, Biomedical and clinical sciences, Nephrotic Syndrome, Ubiquinone, DNA Mutational Analysis, Drug Resistance, Sequence Homology, Protein Kinases/physiology*, Ubiquinone/analogs & derivatives*, Protein Kinases/genetics, Ubiquinone/biosynthesis, Ubiquinone/antagonists & inhibitors, Medical and Health Sciences, Consanguinity, Adrenal Cortex Hormones, 2.1 Biological and endogenous factors, Drosophila Proteins, Exome, Adolescent; Adrenal Cortex Hormones; Amino Acid Sequence; Animals; Cells, Cultured; Child; Consanguinity; Conserved Sequence; DNA Mutational Analysis; Disease Models, Animal; Drosophila Proteins; Drug Resistance; Exome; Fibroblasts; Gene Knockdown Techniques; Humans; Mitochondria; Molecular Sequence Data; Mutation; Nephrotic Syndrome; Podocytes; Protein Kinases; Rats; Sequence Alignment; Sequence Homology, Amino Acid; Ubiquinone; Young Adult; Zebrafish; Zebrafish Proteins, Aetiology, Child, Zebrafish, Cells, Cultured, Conserved Sequence, Fibroblasts/metabolism, Cultured, Podocytes, Ubiquinone/therapeutic use, Biological Sciences, Nephrotic Syndrome/drug therapy, Mitochondria, Amino Acid, Biological sciences, Nephrotic Syndrome/pathology, Podocytes/ultrastructure, Gene Knockdown Techniques, Drosophila Proteins/genetics, Nephrotic Syndrome/genetics*, Podocytes/metabolism, Adolescent, Cells, Immunology, Molecular Sequence Data, Renal and urogenital, 610, Adrenal Cortex Hormones/therapeutic use, Zebrafish Proteins/antagonists & inhibitors, Zebrafish/genetics, Drosophila Proteins/antagonists & inhibitors, Young Adult, Clinical Research, Zebrafish Proteins/genetics, Complementary and Integrative Health, Genetics, Mitochondria/physiology, Animals, Humans, Amino Acid Sequence, Biomedical and Clinical Sciences, Animal, Ubiquinone/metabolism, Health sciences, Adrenal Cortex Hormones/pharmacology, Zebrafish Proteins, Fibroblasts, Rats, Protein Kinases/deficiency, Disease Models, Animal, Nephrotic Syndrome/metabolism, Disease Models, Mutation, Zebrafish/embryology, Protein Kinases, Sequence Alignment
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